Site-Selective Functionalization of Methionine Residues via Photoredox Catalysis

Abstract

Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.

Combining flavin photocatalysis with parallel synthesis: a general platform to optimize peptides with non-proteinogenic amino acids

“…Exploring the utility of our side chain diversification method for other peptides beyond Ac-G-P- Dha -F-NH 2 , we examined H 2 N-G- Dha -H-W-S-Y-G-M-R-P-K-CO 2 H, a Dha-containing peptide which also contains common amino acids found in peptides and proteins that would most likely interfere with our photochemical transformation ( Scheme 1C ). Flavin photocatalysts are known to oxidatively modify C -terminal amino acids via decarboxylation, 32 as well as directly oxidize tyrosine (Y), 33 tryptophan (W), 33,34 histidine (H), 34 and methionine (M) 35 residues. Moreover, radicals are known to modify histidine, tyrosine, and tryptophan amino acids.…”

Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody–drug conjugates

“…Macmillan and co-workers have used lumiflavin (LF) photocatalyst under blue-light (Kessil, 440 nm) to achieve mild, selective and robust functionalisation of a methionine residue with various Michael acceptors. 187 The conjugation proceeds at 23 °C in PBS (pH 7.4)/DMF (19 : 1) at a micromolar concentration of proteins, and gives the conjugates with good conversion yields within 30 min. The 10 equiv.…”

Highly Chemo-, Regio- and Stereoselective Cysteine Modification of Peptides and Proteins with Ynamides

“…[2][3] In addition, chemists have developed a variety of chemical tools to mimic the function of some protein PTMs [4][5][6][7] , and chemical modifications of peptides and proteins have made enormous impact for the developments of biotherapeutics [8][9][10] as well as for basic biological studies [11][12][13][14] . Despite the progress in the chemoselective bioconjugation of previously unexplored amino acid side chains, including serine (Ser) 15 , selenocysteine (Sec) [16][17] , histidine (His) 18 , methionine (Met) [19][20][21][22] , selenomethionine (Sem) 23 , tyrosine (Tyr) [24][25][26][27][28] and tryptophan (Trp), [29][30][31] lysine (Lys) [32][33][34][35][36] and cysteine (Cys) [37][38][39][40][41] are still the preferred residues for chemical protein modification due to their unique nucleophilicity [42][43] . While Lys is highly common in protein sequences (~6% human proteins sequences 44 ), many of which are solvent exposed, Cys is one of the least frequent amino acids in proteins (~ 1.7%)...…”